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Int. J. Mol. Sci. 2015, 16(2), 3071-3094; doi:10.3390/ijms16023071

Pacemaker Activity of the Human Sinoatrial Node: An Update on the Effects of Mutations in HCN4 on the Hyperpolarization-Activated Current

Department of Anatomy, Embryology and Physiology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
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Author to whom correspondence should be addressed.
Academic Editor: Emil Alexov
Received: 22 December 2014 / Accepted: 22 January 2015 / Published: 29 January 2015
(This article belongs to the Collection Human Single Nucleotide Polymorphisms and Disease Diagnostics)
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Abstract

Since 2003, several loss-of-function mutations in the HCN4 gene, which encodes the HCN4 protein, have been associated with sinus node dysfunction. In human sinoatrial node (SAN), HCN4 is the most abundant of the four isoforms of the HCN family. Tetramers of HCN subunits constitute the ion channels that conduct the hyperpolarization-activated “funny” current (If), which plays an important modulating role in SAN pacemaker activity. Voltage-clamp experiments on HCN4 channels expressed in COS-7, CHO and HEK-293 cells, as well as in Xenopus oocytes have revealed changes in the expression and kinetics of mutant channels, but the extent to which especially the kinetic changes would affect If flowing during a human SAN action potential often remains unresolved. In our contribution to the Topical Collection on Human Single Nucleotide Polymorphisms and Disease Diagnostics, we provide an updated review of the mutation-induced changes in the expression and kinetics of HCN4 channels and provide an overview of their effects on If during the time course of a human SAN action potential, as assessed in simulated action potential clamp experiments. Future research may solve apparent inconsistencies between data from clinical studies and data from in vitro and in silico experiments. View Full-Text
Keywords: sinoatrial node; pacemaker activity; funny current; hyperpolarization-activated current; HCN4; ion channelopathies; action potential clamp; computer simulation sinoatrial node; pacemaker activity; funny current; hyperpolarization-activated current; HCN4; ion channelopathies; action potential clamp; computer simulation
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Verkerk, A.O.; Wilders, R. Pacemaker Activity of the Human Sinoatrial Node: An Update on the Effects of Mutations in HCN4 on the Hyperpolarization-Activated Current. Int. J. Mol. Sci. 2015, 16, 3071-3094.

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